Reduction of acyl glucuronidation in a series of acidic 11β-HSD1 inhibitors: the discovery of AZD6925

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Metabolic syndrome is a combination of medical disorders that, when occurring together, increases the risk of developing cardiovascular disease and diabetes. It has been previously suggested that elevated levels of the hormone cortisol can contribute to the development of the metabolic syndrome.

11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an NADPH dependent reductase that converts the glucocorticoid inactive hormone cortisone to the glucocorticoid active hormone cortisol. As such, inhibition of this enzyme has been proposed as a potential target for the treatment of obesity and other contributors to the metabolic syndrome.

In this paper James S. Scott and colleagues report the optimisation of a carboxylic acid class of inhibitors from AZD4017 to the development candidate AZD6925. The novel acidic inhibitors of 11b-HSD1 show excellent pharmacokinetic profiles, and based on the reduced acyl glucuronidation liability and the overall profile, Scott et al. select one compound selected for development as AZD6925 which is to be progressed into toxicity studies.

Reduction of acyl glucuronidation in a series of acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors: the discovery of AZD6925
James S. Scott et al.
DOI: 10.1039/C2MD20154B

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